Tranilast (n-[3,4-dimethoxycinnamoyl]anthranilic acid) is an anti-fibrotic agent used in Japan for the treatment of fibrotic skin disorders such as keloids [8] and scleroderma [9]. Although the precise mechanisms and mode of action are incompletely understood, its ability to inhibit ERK phosphorylation [20], a major intermediate in the TGF-β signalling pathway, may underlie its antifibrotic effects, with known actions of tranilast including the inhibition of TGF-β-induced extracellular matrix production in a range of cell types [10, 11, 14, 16]. Tranilast has also been shown to attenuate TGF-β-induced collagen synthesis in cardiac fibroblasts using an experimental model of diabetic cardiac disease [15].
Fibrosis is a common response to a range of tissue insults that may lead to organ dysfunction. Diseases that are characterised by such pathological fibrosis include hepatic cirrhosis, pulmonary interstitial fibrosis, glomerulonephritis, heart failure (ischaemic and non-ischaemic), diabetic nephropathy, scleroderma, excessive scar tissue post surgery or device insertion, progressive kidney disease, glomerulonephritis, hypertension, heart failure due to ischaemic heart disease, valvular heart disease or hypertensive heart disease and hypertrophic scars. In addition, the elaboration of pathological matrix also has a role in fibroproliferative tumor progression and metastasis.
Diabetic subjects have a two- to fivefold increase risk of developing heart failure [1]. In addition to ischaemic heart disease, heart failure in diabetes is also associated with a cardiomyopathy, independent of coronary artery disease [2]. This so-called “diabetic cardiomyopathy” is characterised histologically by myocardial fibrosis with reduced myocardial elasticity, impaired contractility and overt cardiac dysfunction [3-6]. Accordingly, strategies that reduce the pathological accumulation of extracellular matrix have been advocated as potential therapies for the treatment and prevention of heart failure in both diabetic and nondiabetic states [7].
Current treatment of chronic heart failure focuses on the modulation of the neurohormonal activation that typically develops in response to the evolving functional abnormalities. However, despite such therapy, frequently used in combination, cardiac dysfunction continues to progress in the majority of patients. Given the importance of pathological fibrosis in adverse cardiac remodelling, a potential role of antifibrotic agents has been suggested [16]. Studies conducted over more than a decade have consistently indicated a major role for the prosclerotic growth factor, transforming growth factor-β (TGF-β) in organ fibrosis and dysfunction [17], such that blockade of its expression and action represent an important therapeutic target.
Tranilast has also been shown to reduce inflammation in allergic diseases, such as allergic rhinitis and bronchial asthma, etc. [42].
In addition, tranilast has been shown to have anti-proliferative activity [43, 44].
However, it has recently been shown [19] that genetic factors in certain patients, specifically a Gilbert's syndrome UGT1A1 variant, confers susceptibility to tranilast-induced hyperbilirubinemia. Such hyperbilirubinemia may be associated with tranilast itself or the formation, in vivo, of the following tranilast metabolite

It would be useful to provide further compounds with potential anti-fibrotic, anti-inflammatory, and anti-proliferative or anti-neoplastic activity for the treatment or prevention of diseases associated with fibrosis diseases characterised by inflammation and neoplastic disease (both benign and malignant), and as alternatives/adjuncts to tranilast.
It is an object of the present invention to overcome or at least alleviate one or more of the difficulties and/or deficiencies related to the prior art.